{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T15:08:31Z","timestamp":1788793711157,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research","award":["25K12016"],"award-info":[{"award-number":["25K12016"]}]},{"award":["25K12016"],"award-info":[{"award-number":["25K12016"]}],"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Colorectal cancers (CRCs) include stroma-dominant tumors with desmoplasia and differentiated, gland-forming tumors with little stroma. We asked whether this difference reflects stromal abundance alone or also involves a distinct cancer cell state. HEST-1K sections were classified as M-type (stroma-dominant; five patient\/tissue units) or D-type (differentiated and cancer cell-dominant; seven units). Prespecified EMT\/pEMT, ECM\/integrin, YAP\/TAZ-TEAD, and DTP\/persister gene sets were examined across spatial, bulk, and single-cell datasets and patient-derived malignant ascites cultures. M-type tumors contained broader CAF-rich compartments and higher activity of all four programs in EPCAM\/KRT-high regions, including epithelial-dense tumor cores. Activity was greatest near CAF-rich areas. In GSE39582, EMT\/pEMT, ECM\/integrin, DTP\/persister, and invasive epithelial programs were independently associated with recurrence. Ascites-derived cultures from stroma-dominant tumors showed higher ECM\/integrin and survival programs. Independent institutional analyses supported the public data findings: focused real-time PCR showed higher MAPK\/TGF-beta-related gene expression in M-type-derived than in D-type-derived ascites cells, and IHC showed stronger epithelial CD44v6 expression in M-type primary tumors and metastatic lymph node lesions. CAF co-culture increased VIM-promoter activity. These findings characterize stroma-dominant CRC as a spatially organized ecosystem in which a CAF-rich compartment is associated with stress-adapted cancer cell programs. Its poor prognosis may therefore involve not only stromal abundance but also a morphology-associated cancer cell state detectable after dissemination.<\/jats:p>","DOI":"10.3390\/biom16091261","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:05:26Z","timestamp":1788224726000},"page":"1261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stroma-Dominant Colorectal Cancer Harbors CAF-Rich Spatial Architecture and EMT-Associated Cancer Cell Plasticity Detectable After Dissemination"],"prefix":"10.3390","volume":"16","author":[{"given":"Shuji","family":"Kitagawa","sequence":"first","affiliation":[{"name":"Department of Digestive Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Naoki","family":"Mimura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Hironobu","family":"Kambara","sequence":"additional","affiliation":[{"name":"Department of Digestive Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Masaaki","family":"Hori","sequence":"additional","affiliation":[{"name":"Department of Digestive Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Erina","family":"Yamanishi","sequence":"additional","affiliation":[{"name":"Department of Digestive Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Ayako","family":"Ogo","sequence":"additional","affiliation":[{"name":"Department of Digestive Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Tatsushi","family":"Shiomi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7901-8374","authenticated-orcid":false,"given":"Kazuhiko","family":"Yoshimatsu","sequence":"additional","affiliation":[{"name":"Department of Digestive Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Tomio","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Digestive Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2891-0789","authenticated-orcid":false,"given":"Shuya","family":"Yano","sequence":"additional","affiliation":[{"name":"Department of Digestive Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat. 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